Epigenetics, asking questions, and why failure teaches us more than success

Epigenetics, or the study of changes in organisms caused by modification of gene expression rather than alteration of the genetic code itself, is a very important and complex research interest. Currently, we are just now starting to understand how and when epigenetic information is passed from generation to generation through work done at the Mosher lab. At the Mosher lab, plant sciences are utilized to their full potential so advancement in the study of genetics/epigenetics can occur. Today, we are joined by fellow scientist Dr. Rebecca Mosher. Dr. Mosher is the Associate Director at the School of Plant Sciences and Associate Professor of Genetics, Plant Sciences, and Applied Bioscience here at the University of Arizona. Dr. Mosher is also a collaborator and member of the BIO5 Institute. 

Your work is really fascinating, and I want to talk about how it exemplifies the BIO5 model of an interdisciplinary approach to things. Tell me a little bit about what brought you back to the University of Arizona. I think you've got your undergraduate degree here, am I right about that? 

Yeah, I grew up in Tucson. I went to Sabino High School, and I went to the UofA. I'm actually a third generation Wildcat, so my mom was a chemistry major in the 60s, one of the few female chem majors. She was one of the female chem students back then, and her father was a pharmacy professor. I grew up on campus, you know, going to chemistry camp, things like that. Math camp as well, and then came here as an undergraduate. Then I finally left for a while, but with family in Tucson, I really wanted to come back. UA was a top choice when I went looking for faculty positions.

It sounds like early on you were positioned in the intersection of a STEM related future. Was there, at any point, a hesitation to follow in these footsteps, or was that kind of just a natural progression?

No, it's always been something I've loved. I know sometimes many students can be inspired by hearing the different paths that people take, and then it takes some time to find out. In my case, I really did always know that this is what I wanted to do. That was easy for me.

I credit a lot of it with being on campus as a high school student. I competed in the science fair and was involved in the high school biology research program, which is a part of (e burt?). Even as a 15-16 year old, I was in laboratories learning about molecular biology, interacting with graduate students. Then I was an undergrad, and when you're taking some courses, studying, and taking exams, it makes STEM a little less interesting when that's the aspect of what you're doing, but I already knew what research in a lab was like. I could push through the parts that were less appealing to me because I knew that's where I wanted to get to. That's something that I try to do a lot; not just have undergraduate research opportunities in my lab, but to get students as young as possible and show them this is what the career looks like, asking “do you want to work towards this career?”

Our BIO5 KEYS program brings high schoolers to campus and their experience really does take away some of the mystery of if this is something they want to do, which binds those students to the University very early. Now, fast forward to today. You essentially are a plant scientist, specifically focused in the area of epigenetics. For those of us that are not scientists, talk a little bit about what epigenetics is. I know it's a newer terminology and science as it relates to genetics and genomics. How do those things all interplay, and how did you find your way to that?

There's many definitions of epigenetics, and sometimes people fight over them. I'd say a commonly agreed idea is that epigenetics are chemical modifications, either of the DNA itself or very near to the DNA, that affect whether that DNA is going to be used or not. Sometimes non-scientists aren't as conscious of the fact that every cell in your body has the same DNA, meaning it has the same set of genes. The genes that are important to produce skin cells, though, are different than the genes that are important to produce your liver. Some genes are turned on everywhere, and many other genes are only turned on in particular places or under particular conditions. When you're hungry, a different set of genes get turned on, and that process is called gene regulation. One of the ways that genes can be regulated is by these little chemical marks. My lab studies mostly DNA methylation, and those chemical marks can be passed down when a cell divides because they're physically attached to the DNA. That DNA methylation then is in both of the daughter cells. What really interests me is how those marks aren't just passed through cell division, say in one organism, but the way they might get passed from a parent to an offspring from one generation to the next. That’s my particular focus.

You went through your postdoc education, and you've won some really prestigious awards and have published. How did you know that was going to be where you ended up? Was it a focus of your postdoc program? 

When I started graduate school, I would say epigenetics existed, but it wasn’t a major topic at all. I went to graduate school in North Carolina where there are many great universities, and all of the plant molecular biologists at those universities would gather each fall, alternating between the mountains and the beach, which is a very nice thing about North Carolina. We'd had this North Carolina plant molecular biology retreat, and the first year that I went to it, the speaker was a man named David Baulcombe. He had just made these amazing discoveries about small RNAs which are, in part, what's triggering methylation in plants. He was like our keynote speaker, and he gave this great talk. I was just really hooked on it. It became a really important part of plant molecular biology and really, molecular biology in general over the next few years.  Because I was in a genetics program, I had many other colleagues who were interested in it. A few years later, we as students hosted a symposium on the topic, so it’s something I really became interested in. When I went looking for postdocs, David Baulcombe was one of those on my list. I was also very interested in going even farther from Arizona, going to Europe for a postdoc, and he's in the UK. Actually, that is where I ended up postdoc. Again, I guess it's another case where I got bit by the bug early, and then things just kind of worked out.

You have surrounded yourself with experts in the direction that really intrigued you, but how does that feel when you're attempting these scientific goals and projects? There’s a lot of people that don't know or don't understand, so what is your goal in moving this field forward? What are some of the things that will help all kinds of scientists as this goes further along?

It's certainly the case in the early days of the discovery of small RNAs. If I didn't say it, David Baulcombe was one of the first people to see small RNAs. We had no idea that they were out there at all, and it turns out, they're not just in plants. They are in a wide variety of organisms doing a lot of very interesting things. We even have therapeutics used on humans now based on these small RNAs. Fundamentally, I like to study very basic concepts in biology, and just understand stuff. Sometimes I say that I never grew out of that phase of a child. I'm always like, “why, why?” I just want to know stuff, and I think you can never predict when a discovery that you make will have these really wide connections that can affect many, many, many things. I've also nearly always focused on plants because I think plants are just the most amazing and important organisms. I am aware that if we understand a bit about how epigenetic marks are passed from one generation to the next, and even thinking more broadly about how the information is encoded in the genome passed from one generation to the next; that even if the mechanism might be different in humans, or in starfish, or whatever other organism out there, maybe the general concepts will be the same. 

I am fascinated by how much of what you're learning can be potentially applied to other living organisms and human beings. How does the interdisciplinary environment in BIO5 and at the University of Arizona help you in your work?

I think one of the ways that I find it most helpful is in techniques and approaches. As someone who's studying fundamentally molecular biology, and what I mean by that is, a lot of DNA, how DNA works, how we measure what genes get turned on and off. DNA is DNA. Whatever organism you're looking at, it's the same. If I have colleagues in the Biochemistry department or up at the med school who have developed a new approach to look at some aspect of molecular biology, it's usually fairly easy to adopt the protocols to plants. Same thing: we might have approaches that we've been working on that will apply to their system. On campus, we have a group called the RNA Salon, which is all of the RNA biologists on campus getting together once a month. That's been one of the things that we've been able to share. There are different approaches for how to deal with RNA turned on, which is the product that's made with DNA. That's been helpful, people from all across campus.

I quite like our name as well. When the group was actually started, I think we were called the RNA Club, or something like that. Then the genetics who funds us, which is probably the RNA Society, they started nationwide calling these RNA Salons, and it makes me think we're like in Paris. The other thing that comes from it, just very pragmatically: we even use equipment, a lot of equipment, from colleagues and other departments because some of this is very expensive or specialized. You want to use it as much as possible all the time, so that's also very helpful, those interdisciplinary connections.

I'm switching gears a little bit because I know that being a scientist isn't enough work for you. You also have a great passion for teaching. I know you're the winner of the College of Agriculture and Life Sciences Bart Cardon Early Career Faculty Teaching Award. Congratulations on that, that’s amazing! Talk a little bit about how you incorporate this goal of being a researcher, moving the needle in your field of interest, and then also helping to develop that next generation of scientists. I know you talked about starting that process early, but what are some of the specific ways you do that?

Yeah, it's definitely a balancing act, I guess. I am lucky enough now to be teaching pretty close to my area, so I teach plant genetics and genomics to advanced undergraduates and beginning graduate students. It's a topic that I love, it's really easy to be energized about it, which I think helps. It's also an area that moves very quickly, and I find that, more than in previous courses, I have to redesign a bit every year. That process helps me stay on top of things. One of the things that I've incorporated, because I think it's so important for learning, is even though it's technically a lecture course, every week students are doing activities. As much as possible, I'm giving them the type of genomic data that we use nowadays. I've scaled everything down into small sizes, because you need a lot of computational power for the full data sets, but I want them hands-on understanding that this is what a genome looks like, this is how a genome behaves. Particularly for the graduate students, this is how we know that we know this is what a genome looks like. I think that, for me, the transition from undergrad to graduate school is no longer about just gathering knowledge, that “how do you know that is true?”, which is something we need to be teaching to our undergraduates at all levels, science and otherwise, given our current world state; “How do you know something is true?”

One of the things I found most difficult in this class, actually, is that the students come in saying, “This is the corn genome, I know, I can download it from that website. This is the corn genome.” but to have them understand that that sequence is our best approximation of the corn genome, and corn is an important one, we've done pretty well with it, but pick some other crop. Black eyed peas, cow peas are very common, and ask, “is that really the entirety of that genome? Or are there pieces missing? Is there a possibility that two pieces got stuck together in the wrong direction?” All of these kinds of things happen in genomes a lot. I want them to understand that process of how to put a genome sequence together because they probably do it at some point. I also want them to really question everything they're seeing because inevitably, you'll do an experiment, and something will seem not quite right. You assume you've done something wrong when in reality, your underlying assumption that that genome was exactly what it should be is the error. I'm teaching genomics, so we talk about genomes, but I think that's true with many, many things: getting them to really question.

I also try to weave into it is, it’s not pointing out, “oh, look, there's an error in this gene, and they made a mistake. That's wrong.” It’s pointing out, “this is the best possible that you can have at the time, and it might still be wrong, and that the work that you do might be the same.” You think you're right, you've done the best that you can, but you might be wrong, and that's okay, because then you learn something and you move on to the next step. I often try to, when I'm talking through my research, point out to students times when we were very convinced this particular gene was only going to be found in these particular species, had great reasons why that was gonna be the case, and we went looking, and it was wrong. The gene was absolutely everywhere. I point out to them where we thought we were going was totally wrong, so we went somewhere else. I also have a paper, my postdoc paper, published in Nature that I think is now substantially wrong. We have just learned more. I mean, everything that's in it is correct, but our interpretation of that has changed, and that's just totally okay. You gotta be happy being incorrect sometimes and not knowing things, because that's the way you get even better.

I love that, I think you need to go and talk in front of every single class at the University of Arizona. It is so fundamental to building people's self esteem for the right reasons and the right reasons for them, you know, going along in a career path. 

Well, this is certainly not just me, right? This is the concept of growth mindset, where you never think about you being good at some things or bad at other things. That in anything, you can get better at it. There's also, I don't know where this was coined, but the idea that fail, as a word, stands for “First Attempt In Learning.” You know, you have to make mistakes in order to learn something.

That’s amazing. We found that you once wrote a blog post titled “Combatting the Imposter Syndrome in academic science – you probably are as smart as they think!” What spurred you to pen that and put that out there? What was the impetus for that?

When I was finishing up my postdoc and on the job market, actually I might have even accepted the position at UA, I was at a conference talking with a very prominent scientist in my field. It was breakfast, I remember. He introduced me to an NIH program officer, and I don't remember exactly what I said to him in that conversation, but I obviously said something about being really unsure that I was going to be able to do anything good as a faculty member. He just looked at me and said, “Becky, have you heard of the imposter syndrome?” He explained it to me. I had never heard, never known about it before. If any of our listeners don't know, it's the kind of persistent feeling that you're an imposter, that you're not as good as everybody thinks you are. It was like, earthquake level experience. I've learned more about it since then. I attended a really great workshop run by the Vice Provost for Academic Affairs Office, and I really got involved with that, further developing that workshop, and actually helped put it on here at U of A. I've done it sometimes at other universities when I'm on a seminar visit just to enlighten people, because the thing about impostor syndrome is everybody who feels it, which is many people, keeps it quiet. It’s very easy to recognize in other people. There's some concrete strategies that you can do to help fight those thoughts. Mostly, I think it's just letting people know about it, supporting them, and understanding that it's super common. Some people hate the term because it sounds like a syndrome, like there's something wrong with you. I think it's just a way of acknowledging feelings that many of us have.

I think it's particularly interesting from an academic science perspective. When I give a workshop on it now, it's from that perspective, because we view ourselves as very logical people who take in evidence and draw measured conclusions. You can take that as a way of showcasing to people what you're feeling is somewhat illogical. It's natural, but it doesn't make logical sense. One of my favorites is the argument that people have sometimes, “oh, my mentor tells me that I've done really good work, they're really happy, but they don't know. They're so smart, they don't know how stupid I am.” And it's like, if you value this person, and you think that they are this smart, accomplished scientist mentoring you, then you need to trust them. But no, it's “I'm so stupid that I'm able to fool them.” It's just not logical.

That’s amazing, and thank you for your help in that. So tell me, what's next for your work? What's happening in the next six months that you're excited about?  

The main thrust of the research right now is looking at these tiny small RNAs. They’re only about 24 nucleotides long, which is very small, and they decide where this DNA methylation gets placed in the genome. What we're particularly interested in are these three different tissues in the seed. There's the embryo that's going to grow into the plant when that seed germinates, there's something called endosperm which is food for that embryo, and then there's a seed coat wrapping the whole thing up. I sometimes do a hands-on science thing with kindergarteners about seeds, and I tell them that the mama plant sends her baby out with lunch and a jacket; the endosperm to feed it and the seed coat. What's interesting is that coat is genetically identical to the mother, but the endosperm also carries dad's genes. It's a product of fertilization. It's actually very much like placenta in humans, which is also a product of fertilization. You get these interesting interactions between the seed coat and that endosperm, and we think that the seed coat might be producing small RNAs, that it's moving into the endosperm to help tell the endosperm how to grow and develop, how much food does this baby need and the next generation. I'm really simplifying and personifying, but you kind of get the idea. 

I'm really interested in this area in particular because this is the first time the maternal and the paternal genome come together at fertilization. That endosperm has to grow and develop very rapidly. In fact, it gets well on its way to development before the embryo starts developing, and so this is like a testbed to decide if the maternal and paternal genomes will be compatible. Can they exist together and create another organism? What can mom's genes from a seed coat maybe give some information to help them be more compatible, and to help that seed be successful? That's kind of the broad idea. We've got a long way to go.

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